DK141964B - METHOD OF ANALOGUE FOR THE PREPARATION OF ISOQUINOLINE DERIVATIVES OR SALTS THEREOF WITH PHYSIOLOGICALLY ACCEPTABLE ACIDS - Google Patents

Description

OD PUBLICATION NOTICE 1 ^ 1964 (tt

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DENMARK <5 ”lntc | i c 07 D 217/06 Section (21) Application No. 4853/75 (22) Filed on 28 · Oct · 1975 (23) Running date 28 Oct. 1975 (44) The application presented and mon

the petition published on 2o · JU-L. 1 9oU

DIRECTORATE OF.

PATENT AND TRADEMARK (3 °) Priority requested from it

Nov. 15-Nov. 1974, 2454198, BE Apr 30 1975e 2519163 * BE

(7i) KNOLL AG, Ludwigshafen am Rhein, PO Box 2.t0805, BE.

(72) Inventor: Albert Westermann, Mohnstr. 46, 67 Ludwigshafen / Rhein, DE:

Prank Zimmermann, Am Wieebrunnen 25 * 6730 Neuetadt-Haardt, DE: Dirk Wuppermann, Hinter den Ruestern 28, 6713 Freinsheim * DE: Ludwig Fried * »rich, Nib elungens tr. 8a, 6831 Bruehl, BE: Manfred Raschack, Donners— bergstr. 7, 6714 Weisenheim am Sand, DE.

(74) Plenipotentiary in the proceedings:

Dansk Patent Kontor ApS. (54) Analogous process for the preparation of isoquinoline derivatives or salts thereof with physiologically acceptable acids.

There are known a number of substances that act on blocking β-receptors, ie. substances that bind to g receptors without activating them. However, these compounds have the disadvantage that the g-blocking effect is either not specifically related to an organ or that their tolerability is not optimal or that the distance between therapeutically effective dose and toxic dose (therapeutic index) is not very large.

The invention relates to an analogous process for the preparation of novel in quinoin derivatives of the general formula E4hh-cho-gh-cho-0.

(I) R 0 p 7 wherein E is a hydro gen atom or a methyl group, R a hydrogen ζ μ atom or a methoxy group and E is an isopropyl or tertiary butyl group, or their salts with physiologically acceptable acids.

This process for preparing the compounds of the general formula X is characterized by providing a compound of the formula e3aJUi -e £ (ii) E o 2 3 5 wherein E and E have the meaning given above and R - CH- or Hal-CH2 -CHOH-, in which Hal is a halogen atom, for reaction with an amine of the general formula E HH -,} wherein E has the above meaning and optionally transfers the thus obtained compound to a salt with a physiologically acceptable acid.

Said reaction may be carried out in the presence or absence of a solvent. Suitable solvents are e.g. lower alcohols, preferably isopropanol.

The reaction is preferably carried out at boiling temperature of the solvent; however, it also succeeds at room temperature.

The novel epoxy and chlorohydrin compounds which serve as starting materials for the preparation of the subject compounds can be prepared in known manner by reacting the corresponding iso-quinoline derivatives with epichlorohydrin.

The present compounds may be used as such or in the form of their salts with physiologically acceptable acids. Suitable acids are e.g. hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, citric acid, tartaric acid, lactic acid, diamidosulfonic acid, mucic acid and maleic acid.

3 141964

The compounds of the invention are characterized by a high β-receptor blocking effect and low toxicity. The β-receptor blocking effect can be demonstrated on the β-receptors of the heart, blood vessel and bronchial system. In particular, the cone of the compounds blocks the β-receptors of the heart, which will probably make them suitable for use against functional cardiac disorders.

The particular β-receptor blocking effect on the heart compared with the effect on the vascular system has been determined by recording ECG and guinea pig blood pressure, respectively (cf. JRC Baird and J. Linnell (1972), J.Pharm.Pharmac. 24 , 880-885, and HR Kaplan, HR and MA Commarato (1973)? Pharmacol.EDcp.Ther. 185, 395-4-05).

To study the effect on broncho-dilating agents, the inhibition of the isoprenaline effect on guinea pig bronchi aliasing system is used (cf. H. Konzett, og. And R. Bossier, (194-0) Arch.e: xp..Path. Pharmak . £ 1, 71-74).

The following substances were used: 2-Acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline (A.), 2-acetyl-1,2,3 , 4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -7-methoD ^-isoquinoline (B), 2-formyl-1,2,3,4-tetrahydro-5- (2- hydroxy7-3-isopropylamino-propoxy) -isoquinoline (C), 2-formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylamino-propoxy) -isoquinol (n) .

2-Formyl-1,2,3,4-tetrahydro-6- (2-hydroxy7-3-isopropylamino-propoxy) -isoquinoline (E), 2-formyl-1,2,3,4-tetrahydro-O-6- (2-Hydo: xy-3-isopropylamino-propo: xy) -7-methoxy-isoquinoline (P), 2-acetyl-1,2,3,4-tetrahydro-6- (2- hydroxy-3-tert-butylamino-propoxy) -7-methoxy-isoquinoline (G), 2-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert-butylamino-pro-poQ7 ) -7-methoDq7-isoquinoline (H).

As comparators, prindolol (e), propanolol (f) and practolol (g) were used.

Table 1 lists the intravenous doses experimentally determined for A, B, E-H and f (effective dose on the β-receptors of the heart, blood vessel and bronchial system = ED heart, ED blood vessels, ED bronchial system).

141964 4

Table 1 ~ ΡΓΠ — Ττρπτιρ.Ττι -

Substance ED heart ED blood vessels a! system A 13 mg / kg 80 mg / kg 71 mg / kg B 5.5 "10"> 40 "E 6.6" 6.5 "P 2.4" 2.8 "G- 7.6" 5, 8 "H 1.5 n 2.9" f 1.2 "1.2" 0.18 "

From these substances the following effects appear:

Jabel 2

Substance Heart: blood vessels Heart: bronchial system Å 1: 6.2 1: 5.5 B 1: 1.8 1:> 7.2 E 1: 1 E 1: 1.2 S '1: 0.8 H 1: 1.9 f 1: 1 1: 0.15

It is seen that the quotients for or, Β, E, P, G and H are significantly more favorable than the quotients for the comparison compound. This is especially true for the ratio of cardiac to bronchial dose, i.e. the use of cardiac effective doses does not adversely affect the bronchius system.

Table 3 shows the superior therapeutic width of the subject compounds relative to known β-receptor blocking agents. The values in column I are similar to those in Table 1 / ED hearts, however, the values are generally lower because the animals were pretreated with reserpine. The toxicity studies were performed on albino mice by intravenous administration. The values obtained are given in column II.

141964 5

Table 5 '- γ-

Substance ED - Heart ID 0 0 C 0.18 mg / kg 148 mg / kg D 0.041 "128" e 0.071 "22.6" f 0.33 "24.4" g__4.37__121

Table 3 shows that, at high efficacy, C and D are only slightly toxic, i.e. compared to the comparative compounds e, f and g have a significantly more favorable therapeutic width. This is for the compounds in question in the order of approx. The comparative compounds, on the other hand, range from about 800 to over 3000. 30 to something over 300.

Functional heart disorders, such as tachycardia or palpitations, tachycardic heart rhythm disorders, extrasystole, angina pectoris, hyperkinetic heart syndrome and hypertension are included as indicative areas for the compounds in question.

Tablets, capsules and orally or parenterally deliverable solutions are suitable for administration. The dose used for oral administration is approx. 1-200 mg, by intravenous administration approx. 0.1-20 mg per human and day.

Preparation of previously described starting materials.

A. K-Acyl isoquinoline derivatives a) 46.0 g of 1,2,3,4-tetrahydro-6-hydroxy-isoquinoline hydrobromide are reacted with 85 ml of formamide for 1 hour at 140 ° C with stirring. After cooling to 100 ° C, 216 ml of water are added, whereby the reaction product crystallizes. 34.0 g of 2-formyl-1,2,354-tetrahydro-6-hydroxy-isoquinoline are obtained, m.p. 185.5-186 ° C (ethanol).

Analogously obtained: 2-Eormyl-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinoline, m.p. 172.5 to 174 ° C.

(B) A mixture of 57.6 g of 1,2,3,4-tetrahydro-6-hydroxyisoquinoin hydrobromide, 22.6 g of anhydrous sodium acetate and 76.6 g of acetic anhydride in 300 ml of methylene chloride is kept in 1 reflux for one hour. He adds 300 ml of water, separates the organic phase and extracts the aqueous phase again with methylene chloride. After evaporation of the methylene chloride-ID extracts, the residue is dissolved in dilute sodium hydroxide solution, stirred for 30 minutes on a boiling water bath, and the reaction product is precipitated by the addition of carbon dioxide.

The suction substance is recrystallized from ethanol. 4-3.5 g of 2-acetyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline are obtained, m.p. 135 DEG-160 DEG C. (ethanol - diisopropyl ether).

B. (3-Chloro-2-hydroxy-propoxy) - and (2,3-epoxy-propoxy) -E-acyl-iso-quinoline derivatives.

a) To a mixture of 26.6 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline and 42.5 g of epichlorohydrin, a solution of 6.8 g is dripped at 60 ° C. sodium hydroxide in 90 ml of water over one hour. The reaction mixture is kept at this temperature for another hour, allowed to cool and extracted several times with methylene chloride. The organic phase dried over sodium sulfate is evaporated and the residue is triturated with diethyl ether. 29.0 g of 6- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetr ahydroiso-quinoline are obtained, m.p. 78-79 ° C (acetic acid ethyl ester - diethyl ether).

Analogously obtained: 2-Acetyl-6- (2,3-epoxy-propoxy) -1,2,3,4-tetr ahydro-iso quinoline, m.p. 69-70 ° C (acetic acid ethyl ester - diethyl ether).

6- (2,3-Epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydro-7-methoxy-isoquinoline, m.p. 121-121.5 ° C (acetic acid ethyl ester).

2-Acetyl-6- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-7-methoxy-isoquinoline, m.p. 111-112 ° C (acetic acid ethyl ester - diisopropyl ether).

b) - A mixture of 22.1 g of 2-acetyl-1 / 2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinoline, 27.8 g of epichlorohydrin and 0.2 ml of piperidine is reacted for 18 hours. at 100 ° C with stirring. After evaporation under reduced pressure to dryness, the residue 7 is taken up

U196A

in 75 ml of chloroform; hydrogen chloride is added and evaporated to dryness. The obtained 2-acetyl-6- (3-chloro-2-hydroxy-propoxy) -1,2,3,4-tetrahydro-7-methoxy-isoquinoline is further processed without purification. .

c) To a mixture of 53 »2 g of 2-formyl-1,2,3,4-tetrahydro-5-hydroxy-isoquinoline and 83.3 g of epichlorohydrin is added dropwise at 60 ° 0: a solution of 13.6 g of sodium hydroxide in 180 ml of water over 1 hour. The reaction mixture is kept at this temperature for another hour, allowed to cool and extracted several times with methylene chloride. The organic phase dried over sodium sulfate is evaporated and the residue is purified by column chromatography over moist silica gel (11.5% water). Elution with a mixture of chloroform-acetic acid ethyl ester (30: 1) and evaporation afforded 59.7 g of 5- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydrohydrocarbonate. isoquinoline as a colorless oil.

Analogously, 2-Acetyl-5- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-isoquinoline (colorless oil) is obtained.

Manufacture of end products.

Example 1

A mixture of 24.7 g of 2-acetyl-6- (2,3-epoxy-propoxy) -1, 2,3,4-tetrahydro-isoquinoline and 73.1 g of tertiary butylamine is maintained for 72 hours with stirring. boiling. It is evaporated to dryness under reduced pressure and the residue is taken up in diethyl ether. After cooling and suction, Mon 25.1 g of 2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert.-butylamino-pr opoxy) - ice o quino 1 in, m.p. 74-75 ° C (acetic acid ethyl ester - diethyl ether).

Analogously obtained: 2-Acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert.butylamino-propoxy) -7-methoxy-isoquinoline, m.p. 97-98 ° C (acetic acid ethyl ester - diisopropyl ether), yield: 85% of theory.

8 µm 2-Eormyl-1,2,3,4-tetr ahydro-6- (2-hydroxy-3-tert.butyl amino-propoxy) -7-methoxy-isoquioolin, m.p. 114-, 5-115.5 ° C (acetic acid ethyl ester - diethyl ether), yield: 87% of theory.

2-Acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -7-methoxy-isoquinoline, m.p. 90-91 ° 0 (acetic acid ethyl ester - diethyl ether), yield: 90% of theory.

2-Acetyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline, m.p. 92-93 ° 0 (acetic acid ethyl ester - diisopropyl ether), yield: 93% of theory.

2-Acetyl-1,2,3,4-t-ether ahydro-5- (2-hydroxy-3-tert-butylamino-propoxy) -isoquinoline, m.p. 99-100 ° C (acetic acid ethyl ester - hexane), yield: 86% of theory.

Example 2

A mixture of 23.3 g of 6- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydro-isoquinoline and 73.1 g of tertiary butylamine is reacted analogously to Example 1. you get the crude base as a colorless oil. To transfer to the neutral mucate, the residue is heated in the tenfold amount of ethanol with an equivalent of mucosal acid (10.5 g) for 30 minutes under reflux. After cooling, 34-, 2 g of 2-formyl-1,2,3,4-tetr ahydro-6- (2-hydroxy-3-tert, butylamino-propoxy) -isoquinoline mucate are obtained, m.p. 173-174-, 5 ° 0 (aqueous methanol - diethyl ether).

Analogously obtained: 2-Eormyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-t is butyalmino-pr opoxy) -isoquinoline mucate, m.p. 215-216 ° C (decomposition) (water - acetone), yield: 93% of theory.

Example 3 23.3 g of 6- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydroisoquinoline are maintained with 59.1 g of isopropylamine in 100 ml of isopropanol for 5 hours while boiling under reflux. Evaporate and tear off the residue with 150 ml of diethyl ether. 27.5 g of 2-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline are obtained, m.p. 56.5 to 58 ° C.

Claims (2)

2-Acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline, m.p. 75-76 ° C (acetic acid ethyl ester - diethyl ether), yield: 79% of theory, m.p. (hydrochloride) 120-121 ° C. 2-Formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -7-methoxy-iso-quinoline, m.p. 100-101 ° C (acetic acid ethyl ester - diisopropyl ether), yield: 97% of theory. 2-Formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline, m.p. 50-51 ° C (diethyl ether), yield: 77% of theory, m.p. (mucate) 104-105 ° C (methanol - diethyl ether). Example 4- The product obtained according to Ilb is heated with 59.1 g of isopropylamine and 100 ml of methanol for 10 hours in autoclave to 100 ° 0. After evaporation under reduced pressure to dryness, the residue is triturated with diethyl ether. After recrystallization of the crude product from acetic acid ethyl ester diethyl ether, there is obtained 8.9 g of 2-acetyl-1,2,3,4-tetΓahydΓo-6- (2-hyciro: 5cy-3-iso-popylamino-popopo: xy) - 7-metho: xy-isoquinol: in, m.p. 89-90 ° C. PATEHIIBÅT. Aualogy process for the preparation of isoquinoline derivatives of the formula R4KH-CHo-CH-CHo-O-k £. wherein R is a hydrogen atom or a methyl group, R is a hydrogen atom or a methoxy group and R 2 is an isopropyl or tertiary butyl group,